α-Hydrazino Acids Inhibit Pyridoxal Phosphate-Dependent Decarboxylases via “Catalytically Correct” Ketoenamine Tautomers: A Special Motif for Chemical Biology and Drug Discovery?
Year: 2025
Type: article
Abstract: We present evidence that supports a ‘correct hydrazone tautomer/Dunathan alignment model’ for how α-hydrazino analogues of α-amino acids inhibit PLP enzymes. Described is the asymmetric synthesis of l - and d -α-hydrazino acid l -lysine analogues and their inhibition of Hafnia alvei lysine decarboxylase (LdcI) via kinetic analysis, stopped-flow spectrophotometry, and cryo-EM. We describe a similar investigation of the important anti-Parkinsonism drug, carbidopa, with its human DOPA decarboxylase (hDdc) target. Evidence is consistent with these three hydrazino analogues forming the catalytically relevant ketoenamine PLP-hydrazone tautomer in their target active sites, with the α-carboxylate groups, though insulated, aligning with the PLP-π-system in a Dunathan-model-like orientation. High-resolution cryo-EM structures of the H. alvei LdcI holoenzyme (pdb 9E0M-2.1Å) and LdcI-bound l - and d -hydrazones (pdb 9E0O-2.0 Å; pdb 9E0Q-2.3Å) and the first X-ray crystal structure of hDdc-bound carbidopa (pdb 9GNS-1.93Å) support this ‘correct tautomer’ model. These insights are expected to guide future PLP enzyme inhibitor development.
Source: ACS Catalysis
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: National Science Foundation, Infrastructures en Biologie Santé et Agronomie, Agence Nationale de la Recherche, European Synchrotron Radiation Facility, Fondation pour la Recherche Médicale, Région Auvergne-Rhône-Alpes, Ministero dell'Università e della Ricerca, National Institutes of Health, Horizon 2020 Framework Programme, European Regional Development Fund, National Institute of General Medical Sciences, National Center for Research Resources
Awards: CBH-EUR-GS, New Approaches to Catalyst Screening and Development, MRI: Acquisition of an X-ray Diffractometer for Research and Training in Chemical Structure-Function Studies, G2028412654, G257580033, New Approaches to Catalyst Screening and Development, G3062878540, G3691506601, G3785593939, Acquisition of a 400 MHz NMR Spectrometer, EXTRAMURAL RES FACILITIES CONSTR, G779591567, G8019230938, Infrastructure Française pour la Biologie Structurale Intégrée, Acquisition of a 600 MHz Nuclear Magnetic Resonance Spectrometer, G9000000179, G9000229905
OpenAlex ID: W4410037455